Functional interactions of the cystine/glutamate antiporter, CD44V and MUC1-C oncoprotein in triple-negative breast cancer cells

Masanori Hasegawa, Hidekazu Takahashi, Hasan Rajabi, Maroof Alam, Yozo Suzuki, Li Yin, Ashujit Tagde, Takahiro Maeda, Masayuki Hiraki, Vikas P. Sukhatme, Donald Kufe

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The xCT light chain of the cystine/glutamate transporter (system XC-) is of importance for the survival of triple-negative breast cancer (TNBC) cells. The MUC1-C transmembrane oncoprotein is aberrantly overexpressed in TNBC and, like xCT, has been linked to maintaining glutathione (GSH) levels and redox balance. However, there is no known interaction between MUC1-C and xCT. Here we show that silencing MUC1-C is associated with decreases in xCT expression in TNBC cells. The results demonstrate that MUC1-C forms a complex with xCT and the CD44 variant (CD44v), which interacts with xCT and thereby controls GSH levels. MUC1-C binds directly with CD44v and in turn promotes stability of xCT in the cell membrane. The interaction between MUC1-C and xCT is further supported by the demonstration that targeting xCT with silencing or the inhibitor sulfasalazine suppresses MUC1 gene transcription by increasing histone and DNA methylation on the MUC1 promoter. In terms of the functional significance of the MUC1-C/xCT interaction, we show that MUC1-C protects against treatment with erastin, an inhibitor of XC- and inducer of ferroptosis, a form of non-apoptotic cell death. These findings indicate that targeting this novel MUC1-C/xCT pathway could represent a potential therapeutic approach for promoting TNBC cell death.

Original languageEnglish
Pages (from-to)11756-11769
Number of pages14
JournalOncotarget
Volume7
Issue number11
DOIs
Publication statusPublished - Mar 15 2016
Externally publishedYes

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Triple Negative Breast Neoplasms
Antiporters
Cystine
Oncogene Proteins
Glutamic Acid
Cell Death
Amino Acid Transport System X-AG
Sulfasalazine
DNA Methylation
Histones
Oxidation-Reduction
Glutathione
Cell Membrane
Light
Genes

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Functional interactions of the cystine/glutamate antiporter, CD44V and MUC1-C oncoprotein in triple-negative breast cancer cells. / Hasegawa, Masanori; Takahashi, Hidekazu; Rajabi, Hasan; Alam, Maroof; Suzuki, Yozo; Yin, Li; Tagde, Ashujit; Maeda, Takahiro; Hiraki, Masayuki; Sukhatme, Vikas P.; Kufe, Donald.

In: Oncotarget, Vol. 7, No. 11, 15.03.2016, p. 11756-11769.

Research output: Contribution to journalArticle

Hasegawa, M, Takahashi, H, Rajabi, H, Alam, M, Suzuki, Y, Yin, L, Tagde, A, Maeda, T, Hiraki, M, Sukhatme, VP & Kufe, D 2016, 'Functional interactions of the cystine/glutamate antiporter, CD44V and MUC1-C oncoprotein in triple-negative breast cancer cells', Oncotarget, vol. 7, no. 11, pp. 11756-11769. https://doi.org/10.18632/oncotarget.7598
Hasegawa, Masanori ; Takahashi, Hidekazu ; Rajabi, Hasan ; Alam, Maroof ; Suzuki, Yozo ; Yin, Li ; Tagde, Ashujit ; Maeda, Takahiro ; Hiraki, Masayuki ; Sukhatme, Vikas P. ; Kufe, Donald. / Functional interactions of the cystine/glutamate antiporter, CD44V and MUC1-C oncoprotein in triple-negative breast cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 11. pp. 11756-11769.
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